Some medical devices, including implanted analyte sensors, drug delivery devices and cell transplantation devices require close vascularization and transport of solutes across the device-tissue interface for proper function. These devices generally include a biointerface membrane, which encases the device or a portion of the device to prevent access by host inflammatory cells, immune cells, or soluble factors to sensitive regions of the device.
A disadvantage of conventional biointerface membranes is that they often stimulate a local inflammatory response, called the foreign body response (FBR), which has long been recognized as limiting the function of implanted devices that require solute transport. The FBR has been well described in the literature.
FIG. 1 is a schematic drawing that illustrates a classical FBR to a conventional synthetic membrane 10 implanted under the skin. There are three main layers of a FBR. The innermost FBR layer 12, adjacent to the device, is composed generally of macrophages and foreign body giant cells 14 (herein referred to as the barrier cell layer). These cells form a monolayer of closely opposed cells over the entire surface of a microscopically smooth, macroscopically smooth (but microscopically rough), or microporous (i.e., less than about 1 μm) membrane. Particularly, it is noted that the membrane can be adhesive or non-adhesive to cells, however its relatively smooth surface causes the downward tissue contracture 21 (discussed below) to translate directly to the cells at the device-tissue interface 26. The intermediate FBR layer 16 (herein referred to as the fibrous zone), lying distal to the first layer with respect to the device, is a wide zone (about 30–100 microns) composed primarily of fibroblasts 18, contractile fibrous tissue 19 fibrous matrixes 20. It is noted that the organization of the fibrous zone, and particularly the contractile fibrous tissue 19, contributes to the formation of the monolayer of closely opposed cells due to the contractile forces 21 around the surface of the foreign body (e.g., membrane 10). The outermost FBR layer 22 is loose connective granular tissue containing new blood vessels 24 (herein referred to as the vascular zone). Over time, this FBR tissue becomes muscular in nature and contracts around the foreign body so that the foreign body remains tightly encapsulated. Accordingly, the downward forces 21 press against the tissue-device interface 26, and without any counteracting forces, aid in the formation of a barrier cell layer 14 that blocks and/or refracts the transport of analytes 23 (e.g., glucose) across the tissue-device interface 26.
A consistent feature of the innermost layers 12, 16 is that they are devoid of blood vessels. This has led to widely supported speculation that poor transport of molecules across the device-tissue interface 26 is due to a lack of vascularization near the interface. See Scharp et al., World J. Surg., 8:221–229 (1984); and Colton and Avgoustiniatos, J. Biomech. Eng., 113:152–170 (1991). Previous efforts to overcome this problem have been aimed at increasing local vascularization at the device-tissue interface, but have achieved only limited success.
FIG. 2 is a schematic view that illustrates a conventional bilayer membrane 28 that has cell impermeable layers that are adhesive to cells. Although the conventional bilayer membrane of this example has allowed some blood vessels 24 to be brought close to the implant membrane 28, the cell impenetrable layers are porous and cells 14 are able to reach pseudopodia into the interstices (e.g., pores) of the membrane to attach to and/or flatten on the membrane, as shown in both FIGS. 1 and 2, thereby blocking transport of molecules (e.g., glucose) across the membrane-tissue interface 26.
This layer of cells 12 forms a monolayer with closely opposed cells 14 having tight cell-to-cell junctions, due to cellular attachment and/or contractile forces 21 of fibrous tissue 19, for example. When this barrier cell layer forms, it is not substantially overcome by increased local vascularization. Although local vascularization aids in sustenance of local tissue over time, the barrier cell layer 12 prevents the passage of molecules that cannot diffuse through the layer. Again, this is illustrated in FIG. 2 where blood vessels can be close to the membrane but analyte transport is significantly reduced due to the impermeable nature of the barrier cell layer. For example, when applied to an implantable glucose sensor, both glucose and its phosphorylated form do not readily transit the cell membrane. Consequently, little glucose reaches the implant membrane through the barrier cell layer.
The known art purports to increase the local vascularization in order to increase solute availability. However, it has been observed that once the monolayer of cells (barrier cell layer) is established adjacent to a membrane, increasing angiogenesis is not sufficient to increase transport of molecules such as glucose and oxygen across the device-tissue interface 26. In fact, the barrier cell layer blocks and/or refracts the analytes 23 from transport across the device-tissue interface 26. Materials or membranes employed in implantable devices are described in Brauker et al. (U.S. Pat. No. 5,741,330), Seare, Jr. (U.S. Pat. No. 5,681,572), and Picha (U.S. Pat. No. 5,564,439).